The senile plaque composed of neurotoxic amyloid- peptide (A  ) is a pathologic characteristic of Alzheimer's disease (AD) ( 1-6 ). In the amyloidogenic pathway, A  is derived from a proteolytic process of amyloid precursor protein (APP), in which APP is cleaved sequentially by  -and ␥ -secretases ( 7 ). Alternatively, the non-amyloidogenic pathway is mediated by ␣ -secretase, which cleaves between amino acids 16 and 17 within the A  domain. This secretase is a member of the ADAM (a disintegrin and metalloprotease) family and produces a soluble fragment of APP generally regarded as ␣ -secretase-cleaved soluble APP (sAPP ␣ ) ( 8, 9 ). Due to the neurotrophic and neuroprotective properties of sAPP ␣ ( 10 ), increasing the APP processing by ␣ -secretase has been suggested as a new strategy for the treatment of AD ( 11 ).APP is a transmembrane protein, and recent studies show that APP processing can be affected by the local membrane environment. The activity of  -site APP cleaving enzyme (BACE) to produce neurotoxic A  is favorable in lipid rafts, which are highly ordered membrane microdomains enriched in cholesterol, sphingolipids, and saturated phospholipids ( 12-17 ). On the other hand, cleavage of APP by ␣ -secretases is known to occur mainly in nonraft domains ( 18 ). Therefore, APP processing can be altered